Abstract
Childhood acute lymphoblastic leukemia (ALL) has an origin in the fetal period which may distinguish it from ALL diagnosed later in life. We wanted to test whether familial risks differ in ALL diagnosed in the very early childhood from ALL diagnosed later. The Swedish nation-wide family-cancer data were used until year 2016 to calculate standardized incidence ratios (SIRs) for familial risks in ALL in three diagnostic age-groups: 0–4, 5–34 and 35 + years. Among 1335 ALL patients diagnosed before age 5, familial risks were increased for esophageal (4.78), breast (1.42), prostate (1.40) and connective tissue (2.97) cancers and leukemia (2.51, ALL 7.81). In age-group 5–34 years, rectal (1.73) and endometrial (2.40) cancer, myeloma (2.25) and leukemia (2.00, ALL 4.60) reached statistical significance. In the oldest age-group, the only association was with Hodgkin lymphoma (3.42). Diagnostic ages of family members of ALL patients were significantly lower compared to these cancers in the population for breast, prostate and rectal cancers. The patterns of increased familial cancers suggest that BRCA2 mutations could contribute to associations of ALL with breast and prostate cancers, and mismatch gene PMS2 mutations with rectal and endometrial cancers. Future DNA sequencing data will be a test for these familial predictions.
Highlights
Childhood acute lymphoblastic leukemia (ALL) has an origin in the fetal period which may distinguish it from ALL diagnosed later in life
While many of these predisposing genes are shared by other hematological malignancies, some are implicated in solid tumors, including ATM, BLM, Fanconi anemia genes, TP53 (Li-Fraumeni syndrome) and N F12
The peak incidence of ALL occurs within the first years after birth which has been suggested to indicate the origin of this disease is in the fetal p eriod[1,16,17]
Summary
Childhood acute lymphoblastic leukemia (ALL) has an origin in the fetal period which may distinguish it from ALL diagnosed later in life. Even though DNA repair genes are prominently present among the predisposing genes, the important group of mismatch repair genes is only represented through the very rare constitutional mismatch deficiency syndrome, manifesting many types of cancers including A LL2,6 In addition to these rare high-risk predisposing genes, genome-wide association studies (GWASs) have identified increasing numbers of common low-risk gene variants in the g ermline[7,8,9]. The second hit takes place postnatally and independently in the twin pairs and may be genetic or involve contribution of immune disturbances and other environmental factors[20] These data show that the developmental timing is etiologically important for ALL and it has implication for treatment and p rognosis[1,16,17]. We wanted to consider family history of ALL with any other cancers according to age at ALL diagnosis, in early and late childhood compared to old age using the most recent update of the Swedish Family-Cancer Database
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